title: Formation of soluble amyloid oligomers and amyloid fibrils by the multifunctional protein vitronectin.
abstract: BACKGROUND
  The multifunctional protein vitronectin is present within the deposits associated with Alzheimer disease (AD), age-related macular degeneration (AMD), atherosclerosis, systemic amyloidoses, and glomerulonephritis. The extent to which vitronectin contributes to amyloid formation within these plaques, which contain misfolded, amyloidogenic proteins, and the role of vitronectin in the pathophysiology of the aforementioned diseases is currently unknown. The investigation of vitronectin aggregation is significant since the formation of oligomeric and fibrillar structures are common features of amyloid proteins.
  
  
  RESULTS
  We observed vitronectin immunoreactivity in senile plaques of AD brain, which exhibited overlap with the amyloid fibril-specific OC antibody, suggesting that vitronectin is deposited at sites of amyloid formation. Of particular interest is the growing body of evidence indicating that soluble nonfibrillar oligomers may be responsible for the development and progression of amyloid diseases. In this study we demonstrate that both plasma-purified and recombinant human vitronectin readily form spherical oligomers and typical amyloid fibrils. Vitronectin oligomers are toxic to cultured neuroblastoma and retinal pigment epithelium (RPE) cells, possibly via a membrane-dependent mechanism, as they cause leakage of synthetic vesicles. Oligomer toxicity was attenuated in RPE cells by the anti-oligomer A11 antibody. Vitronectin fibrils contain a C-terminal protease-resistant fragment, which may approximate the core region of residues essential to amyloid formation.
  
  
  CONCLUSIONS
  These data reveal the propensity of vitronectin to behave as an amyloid protein and put forth the possibilities that accumulation of misfolded vitronectin may contribute to aggregate formation seen in age-related amyloid diseases.
authors.affiliation: Zilhka Neurogenetic Institute, University of Southern California, Los Angeles, California 90033, USA. langen@usc.edu.
authors.forename: Thuzar M
authors.initials: TM
authors.lastname: Shin
authors.forename: J Mario
authors.initials: JM
authors.lastname: Isas
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Hsieh
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
authors.forename: Charles G
authors.initials: CG
authors.lastname: Glabe
authors.forename: Ralf
authors.initials: R
authors.lastname: Langen
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chen